Biologists ID defense mechanism of leading fungal pathogen

HOUSTON, June 25, 2004 -- Molecular biologists at Rice University have discovered a key defense mechanism that the yeast Candida albicans uses against attack by the human immune system. This chink in the armor of Candida, the most common human fungal pathogen, could be exploited with new drugs for both lethal and non-lethal Candida outbreaks, including vaginal yeast infections and thrush.

In the study, researchers ran side-by-side comparisons between Candida and baker's yeast -- an organism that doesn't typically infect humans -- in order to find the genes that Candida uses to protect itself against nitric oxide, or NO. Human immune cells give off NO to slow the growth of yeast colonies. The study, published in this month's issue of the journal Eukaryotic Cell, isolated one gene that appears to play a critical role in Candida's NO defense.

The researchers determined that Candida, unlike baker's yeast, is able to sense the presence of NO and ramp up its defenses. They are currently trying to determine which chemical signals Candida uses to detect the presence of NO.

"Baker's yeast and Candida both have the gene to make NO-scavenging enzymes, but Candida has three copies, and it alone has a mechanism to react to increased NO levels by producing more NO-scavengers," said lead researcher Mike Gustin, associate professor of biochemistry and cell biology. "If we can identify the signaling mechanism it uses, that would give us one more useful target for new drug therapies."

Candida is common in humans. It's estimated that 70 percent of people have Candida colonies in their intestines, mouths or on their skin. In most cases, the organism is commensal, meaning it does not harm people, even though it depends upon them for food. However, colonies of Candida sometimes grow too large, as happens in the case of yeast infections. While not life-threatening, vaginal yeast infections are a common and painful problem for a significant percentage of American women. The oral form of Candida infection, known as thrush, is a common problem for infants.

Candida and other forms of yeast infections can also be deadly. This is a particular concern for people with compromised immune systems, including AIDS patients and patients undergoing certain types of treatment for cancer. In cases where Candida infections spread to the bloodstream, mortality rates climb as high as 50 percent.

Candida's defense against NO relies on enzymes called flavohemoglobins. Gustin's research involved a test of three Candida genes -- CaYHB1, CaYHB4 and CaYHB5 -- that produce the enzymes. Gustin's research group created three mutant strains of Candida, each lacking in one of the genes. The strain lacking CaYHB1 was more susceptible to NO than other strains and it proved less virulent in mice than strains of Candida found in the wild.

In addition to interfering with Candida's signaling process, Gustin's group is working with the research team of Rice biochemist John Olson. Olson, the Ralph and Dorothy Looney Professor of Biochemistry and Cell Biology, specializes in the molecular study of oxygen-trapping compounds. Flavohemoglobins are chemically similar to the hemoglobin found in mammalian blood, and Olson's team is trying to determine precisely how flavohemoglobin attacks NO, in hopes of finding a weakness that can be exploited with drugs.

In addition to Candida, Gustin's group is also interested in finding out whether other fungal pathogens like Aspergillus -- a more deadly species than Candida -- use the same NO defense. Gustin said Aspergillus has two genes that are good candidates for study, and he plans to begin research on them in the fall.

The research was supported by the National Science Foundation. Co-authors of the study include Breanna Ullmann, Hadley Myers, Wiriya Chiranand, Qiang Zhao and Luis Vega, all of Rice; Anna Lazzell and Jose Lopez-Ribot of the University of Texas Health Science Center at San Antonio; and Paul Gardner of Children's Hospital Medical Center in Cincinnati.

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